Santos-Silva Rita, Rosário Marta, Grangeia Ana, Costa Carla, Castro-Correia Cíntia, Alonso Isabel, Leão Miguel, Fontoura Manuel
Department of Pediatrics, Pediatric Endocrinology Unit, Centro Hospitalar S. João, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
Department of Pediatrics, Centro Hospitalar S. João, Porto, Portugal.
J Pediatr Endocrinol Metab. 2019 Nov 26;32(11):1265-1273. doi: 10.1515/jpem-2019-0047.
Background Permanent primary congenital hypothyroidism (CH) can be caused by thyroid dysgenesis or dyshormonogenesis. A molecular genetic study is recommended in dyshormonogenesis, in syndromic hypothyroidism and when there is a family history of CH. The aim of this study was to identify a monogenic etiology for CH in selected individuals from a cohort of primary permanent CH. Methods From an initial cohort of 79 patients with permanent CH (3-19 years), 11 patients were selected for molecular analyses. Nine patients with dyshormonogenesis (normal in-situ gland or goiter) were screened for causative variants, by next-generation sequencing (NGS), in 28 genes known to be responsible for CH. One patient with a family history of CH was screened for the paired-box gene 8 (PAX8) gene and another patient with a syndromic CH was screened for the NKX2-1 gene. Results We found a monogenic basis of disease in eight patients, involving the thyroid peroxidase (TPO) gene (four patients), the thyroglobulin (TG) gene (two patients), and the PAX8 and NKX2-1 genes (one patient each). Two patients were heterozygotes, one harboring a variant in the TG gene and the other in the SLC5A5 gene. In one patient, we found no potential causative variants in any of the 28 genes screened. We described five novel variants: three in the TG gene, one in the NKX2-1 and one in the SLC5A5 gene, all of them classified as pathogenic. Conclusions In eight of the 11 screened patients, a monogenic disease was found. These results highlight the advantage of using an NGS panel and provide further data regarding the molecular basis of CH.
背景 永久性原发性先天性甲状腺功能减退症（CH）可由甲状腺发育不全或激素合成障碍引起。对于激素合成障碍、综合征性甲状腺功能减退症以及有CH家族史的情况，建议进行分子遗传学研究。本研究的目的是在一组原发性永久性CH患者中确定部分个体CH的单基因病因。方法 从最初的79例永久性CH患者（3 - 19岁）队列中，选取11例患者进行分子分析。对9例激素合成障碍患者（原位腺体正常或有甲状腺肿），通过二代测序（NGS）筛查28个已知与CH相关的基因中的致病变异。对1例有CH家族史的患者筛查配对盒基因8（PAX8），对另1例综合征性CH患者筛查NKX2 - 1基因。结果 我们在8例患者中发现了疾病的单基因基础，涉及甲状腺过氧化物酶（TPO）基因（4例患者）、甲状腺球蛋白（TG）基因（2例患者）以及PAX8和NKX2 - 1基因（各1例患者）。2例患者为杂合子，1例在TG基因有变异，另1例在SLC5A5基因有变异。在1例患者中，我们在筛查的28个基因中均未发现潜在的致病变异。我们描述了5个新变异：3个在TG基因，1个在NKX2 - 1基因，1个在SLC5A5基因，所有这些变异均被分类为致病性变异。结论 在11例筛查患者中的8例发现了单基因疾病。这些结果突出了使用NGS panel的优势，并提供了关于CH分子基础的更多数据。
